Dr. Murugappan Ramanathan is a junior faculty member in the Department of Otolaryngology-Head & Neck Surgery at the Johns Hopkins School of Medicine where his clinical practice is dedicated to the medical and surgical management of nasal and sinus disorders. His previous research focused on impaired sinonasal epithelial innate immune responses in patients with chronic sinusitis. With the support of this Mentored Career Development Award, Dr. Ramanathan seeks to better understand the impact of indoor environmental exposure (particulate matter and allergens) on oxidative stress based sinonasal inflammation regulated by the Nrf2 anti- oxidant pathway. Dr. Ramanathan will enhance his research knowledge and skills with coursework in environmental health and air pollution, receive directed mentorship by an interdisciplinary team of experienced researchers, and be immersed in the interdisciplinary research and clinical environments of the Johns Hopkins School of Medicine, Johns Hopkins Bloomberg School of Public Health, and the Center for Childhood Asthma in the Urban Environment. This Career Development Award will provide Dr. Ramanathan with the resources that he needs to become an independent investigator and future leader in environmental exposure related sinonasal inflammation research. Building on his prior research experience in chronic sinonasal inflammation, Dr. Ramanathan has now transitioned his focus towards examining how the indoor environmental pollutants and allergens propagate oxidative stress related sinonasal inflammation. He is also interested in how the novel drug targetable transcription factor, Nrf2, may control the mucosal inflammatory state. In Aim 1a, he will determine the role of Nrf2 in regulating indoor particulate matter (PM) induced sinonasal inflammation in an allergic rhinitis mouse model. Aim 1b will use sinonasal epithelial cells grown in culture from control and chronic sinusitis patients and expose them in vitro to indoor PM or environmental mouse allergen. Subsequently, levels of inflammation, oxidative stress, and Nrf2 dependent antioxidants will be measured. In Aim 1c, Dr. Ramanathan will use asthmatic patients from the existing NIEHS ASTHMA-DIET study and correlate sinonasal levels of inflammation, oxidative stress, and levels of Nrf2 regulated antioxidants after intranasal mouse allergen challenge. Finally, in Aim 2, Dr. Ramanathan will use sulforaphane for chemoprotection to enhance levels of Nrf2 regulated antioxidants in both animal and cell culture models prior to environmental exposures. The process of performing these experiments will provide the candidate with the necessary guidance, coursework, and practical training towards becoming an independent investigator as well as furthering the basic science knowledge of sinonasal inflammation. Public Health Relevance: Chronic rhinosinusitis afflicts greater than 30 million individuals yearly and is among the most common conditions for which patients seek medical care in the US. While the pathogenesis of this disease is multi-factorial, very little research has examined the role of environmental exposure. This proposal will study the role of a critical pathway that may regulate environmentally induced inflammation in the nose and sinus and may ultimately lead to more effective therapies for chronic sinusitis.